<i>In Silico</i> Tools and Approaches for the Prediction of Functional and Structural Effects of Single-Nucleotide Polymorphisms on Proteins: An Expert Review

Yazar, Metin; Ozbek, Pemra

doi:10.1089/omi.2020.0141

Cited by 34 publications

(18 citation statements)

References 153 publications

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“…Transmembrane helix predictions were performed with the DeepTHMMM bioinformatic tool [ 34 ]. The biological effects of the protein mutation were predicted by the PROVEAN tool, and protein stability changes were predicted with the VAPOR tool [ 35 ]. The three-dimensional (3D) models for protein structures of the Fks1 variants were obtained by modelling using the I-TASSER online server [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

Decreased echinocandin susceptibility in Candida parapsilosis causing candidemia and emergence of a pan-echinocandin resistant case in China

Ning

Xiao

Perlin

et al. 2022

Emerging Microbes & Infections

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Candida parapsilosis is becoming a predominant non- albicans cause of invasive candidiasis (IC). Echinocandins are the preferred choice for IC treatment and prophylaxis. Resistance to echinocandins in C. parapsilosis has emerged in several countries, but little is known about the susceptibility profile in China or about mechanisms of resistance. Here, we investigated the echinocandin susceptibilities of 2523 C. parapsilosis isolates collected from China and further explored the resistance mechanism among echinocandin-resistant isolates. Anidulafungin exhibited the highest MICs (MIC 50/90 , 1 and 2 µg/mL; GM, 0.948 µg/mL), while caspofungin showed better activity (0.5 and 1 µg/mL; 0.498 µg/mL). Significantly higher echinocandin MICs were observed among blood-derived isolates compared to others, especially for caspofungin (GM, 1.348 µg/mL vs 0.478 µg/mL). Isolates from ICU and surgical wards also showed higher MICs. Twenty isolates showed intermediate phenotypes for at least one echinocandin. One was resistant to all three echinocandins, fluconazole and voriconazole, which caused breakthrough IC during long-term exposure to micafungin. WGS revealed this isolate carried a mutation S656P in hotspot1 region of Fks1. Bioinformatics analyses suggested that this mutation might lead to an altered protein conformation. CRISPR Cas9-mediated introduction of this mutation into a susceptible reference C. parapsilosis strain increased MICs of all echinocandins 64-fold, with similar results found in the subspecies, C. orthopsilosis and C. metapsilosis . This is the first report of a multi-azole resistant and pan-echinocandin resistant C. parapsilosis isolate, and the identification of a FKS1 S656P conferring pan-echinocandin resistance. Our study underscores the necessity of rigorous management of antifungal use and of monitoring for antifungal susceptibility.

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Section: Methodsmentioning

confidence: 99%

Decreased echinocandin susceptibility in Candida parapsilosis causing candidemia and emergence of a pan-echinocandin resistant case in China

Ning

Xiao

Perlin

et al. 2022

Emerging Microbes & Infections

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“…Among these single-nucleotide polymorphisms (SNPs), non-synonymous single-nucleotide polymorphisms (nsSNPs) cause amino acid residue change in the protein sequence (44,45). Which can cause changes in protein function due to changes in protein structure and folding (46)(47)(48). In silico methods are the most common approach to gathering information about the etiology of prion diseases by researchers (49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Pathological E200K Mutation on Human Prion Protein: A Computational screening and Molecular Dynamic approach

Gharemirshamloo

Majumder

Bamdad

et al. 2022

Preprint

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The Human Prion protein gene (PRNP) is mapped to short arm of chromosome 20 (20pter-12). Prion disease is associated with mutations in the Prion Protein encoding gene sequence. The mutations that occur in the prion protein could be divided into two types based on their influence on pathogenic potential: 1. Mutations that cause disease. 2. Disease-resistance mutations. Earlier studies found that the mutation G127V in the PRNP increases protein stability, whereas the mutation E200K, which has the highest mutation rate in the Prion protein, causes Creutzfeldt–Jakob disease (CJD) in humans and induces protein aggregation. We used a variety of bioinformatic algorithms, including SIFT, PolyPhen, I-Mutant, PhD-SNP, and SNP&GO, to predict the association of the E200K mutation with Prion disease. MD simulation is performed and graphs for RMSD, RMSF, Rg, DSSP, PCA, porcupine and FEL are generated to confirm and prove the stability of the wild type and mutant protein structures. The protein is analyzed for aggregation, and the results indicates more fluctuations in the protein structure during the simulation by the E200K mutation, however the G127V mutation makes protein structure stable against aggregation during the simulation.

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“…In recent years, a lot of software has been developed to predict deleterious nsSNPs through different algorithms and biological considerations, which is cost-effective and fast. At present, we integrated software for predicting damaging nsSNPs SIFT, PANTHER, and SNAP and software for inferring that the damaging effects of disease-related nsSNPs PhD-SNP, PolyPhen-2, SNPS&GO, and I-Mutant 2.0 are relatively mature, which has been widely employed in several previous studies [ 18 , 33 , 34 , 35 , 36 ]. The rationales of the prediction and inference of deleterious nsSNPs rely on considerations of the protein domain and sequence conservation.…”

Section: Discussionmentioning

confidence: 99%

Computational and Mass Spectrometry-Based Approach Identify Deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in JMJD6

et al. 2021

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The jumonji domain-containing protein 6 (JMJD6) gene catalyzes the arginine demethylation and lysine hydroxylation of histone and a growing list of its known substrate molecules, including p53 and U2AF65, suggesting a possible role in mRNA splicing and transcription in cancer progression. Mass spectrometry-based technology offers the opportunity to detect SNP variants accurately and effectively. In our study, we conducted a combined computational and filtration workflow to predict the nonsynonymous single nucleotide polymorphisms (nsSNPs) present in JMJD6, followed by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and validation. The computational approaches SIFT, PolyPhen-2, SNAP, I-Mutant 2.0, PhD-SNP, PANTHER, and SNPS&GO were integrated to screen out the predicted damaging/deleterious nsSNPs. Through the three-dimensional structure of JMJD6, H187R (rs1159480887) was selected as a candidate for validation. The validation experiments showed that the mutation of this nsSNP in JMJD6 obviously affected mRNA splicing or the transcription of downstream genes through the reduced lysyl-hydroxylase activity of its substrates, U2AF65 and p53, further indicating the accuracy of this prediction method. This research provides an effective computational workflow for researchers with an opportunity to select prominent deleterious nsSNPs and, thus, remains promising for examining the dysfunction of proteins.

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In Silico Tools and Approaches for the Prediction of Functional and Structural Effects of Single-Nucleotide Polymorphisms on Proteins: An Expert Review

Cited by 34 publications

References 153 publications

Decreased echinocandin susceptibility in Candida parapsilosis causing candidemia and emergence of a pan-echinocandin resistant case in China

Decreased echinocandin susceptibility in Candida parapsilosis causing candidemia and emergence of a pan-echinocandin resistant case in China

Effects of the Pathological E200K Mutation on Human Prion Protein: A Computational screening and Molecular Dynamic approach

Computational and Mass Spectrometry-Based Approach Identify Deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in JMJD6

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